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Updated: Jan 17, 2026
Author Spotlight: Advanced Integrated Model for Sepsis-Induced Myopathy and Single-Cell Metabolic Analysis
Published on: June 14, 2024
P2X7 Receptor Acts as a Novel Target for Ameliorating Sepsis-Induced Skeletal Muscle Atrophy in Mice Model
Yukun Liu1, Qinxin Liu2,3,4,5, Zhikai Xu2,3,4,5
1Department of Plastic and Aesthetic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Background And Objective:
Sepsis, a systemic inflammatory syndrome, frequently leads to substantial skeletal muscle loss and dysfunction, severely impairing patient prognosis. The P2X7 receptor is an adenosine triphosphate-gated cation channel implicated in inflammation and cell death. Although its role in the immune system has been extensively studied, its expression profile and pathogenic mechanism in sepsis-induced skeletal muscle atrophy remain unclear. This study aimed to investigate the functional role of the P2X7 receptor in sepsis-associated muscle injury and its potential as a therapeutic target.
Methods:
A murine sepsis model was established using cecal ligation and puncture (CLP) surgery. Temporal changes in P2X7 receptor expression in the gastrocnemius (GP) and tibialis anterior (TA) muscles were assessed. Functional studies were performed using P2X7 knockout (P2X7 - / - ) mice and the P2X7-specific antagonist A-740003. Skeletal muscle atrophy, inflammatory responses, and activation of the NLRP3 inflammasome signaling pathway were systematically evaluated through Western blotting, qPCR, hematoxylin-eosin staining, muscle fiber cross-sectional area analysis, and measurement of inflammatory cytokines.
Results:
In the CLP-induced sepsis model, P2X7 receptor expression in both GP and TA muscles was upregulated in a time-dependent manner. P2X7 gene deletion significantly attenuated body weight loss, muscle mass reduction, and muscle fiber atrophy, restored grip strength, and suppressed the expression of atrophy-related genes (Myostatin, Atrogin-1, and MuRF1). Moreover, it markedly reduced IL-6, IL-18, and IL-1β levels in both skeletal muscle and plasma, indicating an anti-inflammatory effect. P2X7 deficiency also significantly inhibited the expression of NLRP3 inflammasome components, caspase-1, and gasdermin D, thereby blocking the pyroptosis signaling pathway. Pharmacological inhibition with A-740003 showed dose-dependent mitigation of muscle atrophy, further supporting the therapeutic potential of targeting P2X7.
Conclusions:
The P2X7 receptor contributes to sepsis-induced skeletal muscle atrophy by promoting inflammation and muscle protein degradation through activation of the NLRP3 inflammasome and pyroptosis pathways. Genetic or pharmacological inhibition of P2X7 significantly alleviates muscle damage and functional loss. These findings provide strong experimental evidence supporting P2X7 as a potential therapeutic target for sepsis-associated myopathy.
Insights
Targeting the P2X7 receptor reduces muscle loss and dysfunction during sepsis. Inhibiting this receptor alleviates inflammation and muscle protein degradation, offering a potential therapeutic strategy for sepsis-associated myopathy.
Area of Science:
- Biochemistry
- Immunology
- Molecular Biology
Background:
- Sepsis causes significant skeletal muscle atrophy and dysfunction, worsening patient outcomes.
- The P2X7 receptor's role in sepsis-induced muscle atrophy is not well understood.
- Investigating P2X7's mechanism in muscle injury is crucial for developing targeted therapies.
Purpose of the Study:
- To elucidate the functional role of the P2X7 receptor in sepsis-associated skeletal muscle injury.
- To explore the potential of targeting the P2X7 receptor as a therapeutic strategy for sepsis-induced myopathy.
Main Methods:
- Established a murine sepsis model via cecal ligation and puncture (CLP).
- Assessed P2X7 receptor expression and utilized P2X7 knockout mice and a specific antagonist (A-740003).
- Evaluated muscle atrophy, inflammation, and NLRP3 inflammasome activation using molecular and histological techniques.
Main Results:
- P2X7 receptor expression increased in skeletal muscles post-CLP.
- P2X7 deficiency or inhibition attenuated muscle atrophy, improved muscle function, and reduced inflammatory cytokine levels (IL-6, IL-18, IL-1β).
- P2X7 inhibition suppressed NLRP3 inflammasome and pyroptosis pathways.
Conclusions:
- The P2X7 receptor exacerbates sepsis-induced skeletal muscle atrophy via NLRP3 inflammasome and pyroptosis activation.
- Genetic or pharmacological P2X7 inhibition effectively mitigates muscle damage and functional decline.
- P2X7 receptor inhibition represents a promising therapeutic target for sepsis-associated myopathy.
